208.\Groenewoud, A. S., Westert, G. P. & Kremer, J. A. M. Value based competition in health care’s ethical drawbacks and the need for a values-driven approach. BMC Health Serv. Res. 19, 256 (2019).

209.\Antonarakis, S. E. et al. Down syndrome. Nat. Rev. Dis. Primers 6, 9 (2020).

210.\ Garavelli, L. & Mainardi, P. C. Mowat-Wilson syndrome. Orphanet J. Rare Dis. 2, 42 (2007). 211.\ Read, A. P. & Newton, V. E. Waardenburg syndrome. J. Med. Genet. 34, 656–665 (1997). 212.\ Pingault, V. et al. Review and update of mutations causing Waardenburg syndrome. Hum.

Mutat. 31, 391–406 (2010).

213.\ Marini, F. et al. Multiple endocrine neoplasia type 2. Orphanet J. Rare Dis. 1, 45 (2006). 214.\ Porter, F. D. Smith–Lemli–Opitz syndrome: pathogenesis, diagnosis and management.

Eur. J. Hum. Genet. 16, 535–541 (2008).

215.\ Christaller, W. A. A., Vos, Y., Gebre-Medhin, S., Hofstra, R. M. W. & Schäfer, M. K. E. L1 syndrome diagnosis complemented with functional analysis of L1CAM variants located to the two N-terminal Ig-like domains. Clin. Genet. 91, 115–120 (2017).

216.\ Forsythe, E. & Beales, P. L. Bardet–Biedl syndrome. Eur. J. Hum. Genet. 21, 8–13 (2013). 217.\ Trang, H. et al. Guidelines for diagnosis and management of congenital central

hypoventilation syndrome. Orphanet J. Rare Dis. 15, 252 (2020).

218.\ Vakkilainen, S., Taskinen, M., Klemetti, P., Pukkala, E. & Mäkitie, O. A 30-year prospective follow-up study reveals risk factors for early death in cartilage–hair hypoplasia.

Front. Immunol. 10, 1581 (2019).

219.\ Robinson, P. N. et al. Shprintzen–Goldberg syndrome: fourteen new patients and a clinical analysis. Am. J. Med. Genet. A 135, 251–262 (2005).

220.\ Bedeschi, M. F. et al. Impairment of di erent protein domains causes variable clinical presentation within Pitt–Hopkins syndrome and suggests intragenic molecular syndromology of TCF4. Eur. J. Med. Genet. 60, 565–571 (2017).

221.\ Naiki, M. et al. MBTPS2 mutation causes BRESEK/BRESHECK syndrome. Am. J. Med. Genet. A 158A, 97–102 (2012).

222.\ Slavotinek, A. M. et al. Mutation analysis of the MKKS gene in McKusick–Kaufman syndrome and selected Bardet–Biedl syndrome patients. Hum. Genet. 110, 561–567 (2002).

223.\ Orphanet. The portal for rare diseases and orphan drugs. orphanet https://www.orpha.net/ consor/cgi-bin/Disease.php?lng=EN (2023).

224.\ Adam, M. P. et al. (eds) GeneReviews [online] https://www.ncbi.nlm.nih.gov/books/ NBK1116/ (2023).

225.\ Jensen, A. R. & Frischer, J. S. Surgical history of Hirschsprung disease. Semin. Pediatr. Surg. 31, 151174 (2022).

226.\ Raveenthiran, V. Knowledge of ancient Hindu surgeons on Hirschsprung disease: evidence from Sushruta Samhita of circa 1200-600 BC. J. Pediatr. Surg. 46, 2204–2208 (2011).

227.\ Goldstein, A. M., Hofstra, R. M. & Burns, A. J. Building a brain in the gut: development of the enteric nervous system. Clin. Genet. 83, 307–316 (2013).

228.\ Bondurand, N., Dufour, S. & Pingault, V. News from the endothelin-3/EDNRB signaling pathway: role during enteric nervous system development and involvement in neural crest-associated disorders. Dev. Biol. 444, S156–S169 (2018).

229.\ Stavely, R. et al. A distinct transcriptome characterizes neural crest-derived cells at the migratory wavefront during enteric nervous system development. Development 150, dev201090 (2023).

230.\Heuckeroth, R. O. Hirschsprung’s disease, Down syndrome, and missing heritability: too much collagen slows migration. J. Clin. Invest. 125, 4323–4326 (2015).

231.\ Ahmad, H. et al. Evaluation and treatment of the post pull-through Hirschsprung patient who is not doing well; update for 2022. Semin. Pediatr. Surg. 31, 151164 (2022).

232.\ Langer, J. C. & Birnbaum, E. Preliminary experience with intrasphincteric botulinum toxin for persistent constipation after pull-through for Hirschsprung’s disease. J. Pediatr. Surg. 32, 1059–1062 (1997).

233.\Svetano , W. J., Lim-Beutal, I. I. P., Wood, R. J., Levitt, M. A. & Rentea, R. M. The utilization of botulinum toxin for Hirschsprung disease. Semin. Pediatr. Surg. 31, 151161 (2022).

Acknowledgements

L.S.C. is supported by grants from the National Institutes of Health (K08DK133673), the American College of Surgeons, and the American Pediatric Surgical Association. A.G. supported by grants (R01DK125047 and R21AI163503) from the National Institutes of Health.

Author contributions

Introduction (L.M. and A.G.); Epidemiology (K.K. and I.de B.); Mechanisms/pathophysiology (L.S.C., L.M. and I.de B.); Diagnosis (R.K., D.B. and L.M.); Management (A.B., L.S.C., J.C.L., L.M. and A.G.); Quality of life (M.P. and K.K.); Outlook (L.S.C. and A.G.); Overview of the Primer (L.M. and A.G.).

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Reviews Disease Primers thanks A. Burns, R. Hotta, P. Tam, T. Wester and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional afiliations.

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

© Springer Nature Limited 2023